Persons with traumatic brain injury (TBI) experience high rates of depression, especially during the first six months following their injuries. Neurological and psychosocial factors appear to contribute to depression in this population. Depression following TBI is associated with poor cognitive, behavioral, and functional outcomes. Preliminary studies suggest that people with TBI and major depression may not respond to antidepressant treatment in the same way as depressed persons without TBI, post TBI depression may respond well to selective serotonin reuptake inhibitor (SSRI) antidepressants, that and effective antidepressant treatment is associated with improvements in health status, neuropsychological function, and post-concussive symptoms. No large randomized placebo-controlled studies have been conducted and basic questions remain about the treatment and outcomes of major depression among persons with traumatic injury. As a consequence, depression is not usually assessed after traumatic brain injury, and optimal rehabilitation guidelines for identifying and treating depression have not been established. To address this gap, the proposed study would follow a large consecutive sample of persons hospitalized for moderate to severe TBI to identify those who develop major depression. With those who develop major depression, a 12-week, randomized, double-blind, controlled trial of sertraline would be conducted. The trial would test the hypothesis that sertraline reduces depression related symptoms, as measured by the Hamilton Rating Scale for Depression. Secondary hypotheses to be tested include whether sertraline leads to greater improvement in neuropsychological test performance, post-concussive symptoms and self-reported health status as measured by the SF 36.